1.1 Cutaneous Squamous Cell Carcinoma

LIBTAYO is indicated for the treatment of patients with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation.

1.2 Basal Cell Carcinoma

LIBTAYO is indicated for the treatment of patients:

• with locally advanced basal cell carcinoma (laBCC) previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate.
• with metastatic BCC (mBCC) previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. The mBCC indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for the mBCC indication may be contingent upon verification and description of clinical benefit.

1.3 Non-Small Cell Lung Cancer

LIBTAYO is indicated for the first-line treatment of patients with non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥ 50%] as determined by an FDA-approved test [see Dosage and Administration (2.1)]), with no EGFR, ALK or ROS1 aberrations, and is:

• locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or
• metastatic.

2.1 Patient Selection for NSCLC

Select patients with locally advanced or metastatic NSCLC for treatment with LIBTAYO based on PD-L1 expression on tumor cells [see Clinical Studies (14.3)].

Information on FDA-approved tests for the detection of PD-L1 expression is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosage of LIBTAYO is 350 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

2.3 Dosage Modifications for Adverse Reactions

No dose reduction for LIBTAYO is recommended. In general, withhold LIBTAYO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue LIBTAYO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for LIBTAYO for adverse reactions that require management different from these general guidelines are summarized in Table 1.

2.4 Preparation and Administration

• Visually inspect for particulate matter and discoloration prior to administration. LIBTAYO is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. Discard the vial if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of translucent to white particles.

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

LIBTAYO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

Early identification and management of immune‐mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue LIBTAYO depending on severity [see Dosage and Administration (2.3)]. In general, if LIBTAYO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

5.2 Infusion-Related Reactions

Severe infusion-related reactions (Grade 3) occurred in 0.1% of patients receiving LIBTAYO as a single agent. Monitor patients for signs and symptoms of infusion-related reactions. The most common symptoms of infusion-related reaction were nausea, pyrexia, rash and dyspnea.

Interrupt or slow the rate of infusion or permanently discontinue LIBTAYO based on severity of reaction [see Dosage and Administration (2.3)].

5.3 Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action, LIBTAYO can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LIBTAYO and for at least 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Warnings and Precautions reflect exposure to LIBTAYO as a single agent in 810 patients in three open-label, single-arm, multicohort studies (Study 1423, Study 1540 and Study 1620), and one open-label randomized multi-center study (Study 1624). These studies included 219 patients with advanced CSCC (Studies 1540 and 1423), 132 patients with advanced BCC (Study 1620), 355 patients with NSCLC (Study 1624), and 104 patients with other advanced solid tumors (Study 1423). LIBTAYO was administered intravenously at doses of 3 mg/kg every 2 weeks (n=235), 350 mg every 3 weeks (n=543), or other doses (n=32; 1 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, 200 mg every 2 weeks). Among the 810 patients, 57% were exposed for ≥ 6 months and 25% were exposed for ≥ 12 months. In this pooled safety population, the most common adverse reactions (≥15%) were musculoskeletal pain, fatigue, rash, and diarrhea. The most common Grade 3-4 laboratory abnormalities (≥2%) were lymphopenia, hyponatremia, hypophosphatemia, increased aspartate aminotransferase, anemia, and hyperkalemia.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cemiplimab-rwlc in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Anti-drug antibodies (ADA) were tested in 823 patients who received LIBTAYO. The incidence of cemiplimab-rwlc treatment-emergent ADAs was 2.2% using an electrochemiluminescent (ECL) bridging immunoassay; 0.4% were persistent ADA responses. In the patients who developed anti-cemiplimab-rwlc antibodies, there was no evidence of an altered pharmacokinetic profile of cemiplimab-rwlc.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of LIBTAYO have not been established in pediatric patients.

8.5 Geriatric Use

Of the 810 patients who received LIBTAYO in clinical studies, 32% were 65 years up to 75 years and 22% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 219 patients with mCSCC or laCSCC who received LIBTAYO in clinical studies, 34% were 65 years up to 75 years and 41% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 132 patients with BCC who received LIBTAYO in Study 1620, 27% were 65 years up to 75 years, and 32% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

12.1 Mechanism of Action

Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.

Cemiplimab-rwlc is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

12.3 Pharmacokinetics

Cemiplimab-rwlc pharmacokinetic data were collected in 1062 patients with various solid tumors in a population pharmacokinetic analysis. The pharmacokinetics of cemiplimab-rwlc were linear and dose proportional in the dose range of 1 mg/kg to 10 mg/kg LIBTAYO administered intravenously every 2 weeks.

At 350 mg every 3 weeks, the mean cemiplimab-rwlc concentrations (coefficient of variation, CV%) at steady-state ranged between a minimum concentration of 61 mg/L (45%) and a maximum concentration of 171 mg/L (28%). Steady-state exposure is achieved after 4 months of treatment.

In patients with CSCC, cemiplimab-rwlc steady-state exposure at 350 mg every 3 weeks was comparable to the exposure at 3 mg/kg every 2 weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the potential of cemiplimab-rwlc for carcinogenicity or genotoxicity.

In a 3-month repeat-dose toxicology study in sexually mature cynomolgus monkeys, there were no cemiplimab-rwlc-related effects on fertility parameters (menstrual cycle, semen analysis, or testicular measurements) or in male or female reproductive organs at doses up to the highest dose tested, 50 mg/kg/week (approximately 5.5 to 25.5 times the human exposure based on AUC at the clinical dose of 350 mg once every 3 weeks).

13.2 Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

14.1 Cutaneous Squamous Cell Carcinoma (CSCC)

The efficacy of LIBTAYO in 219 patients with metastatic (nodal or distant) cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who were not candidates for curative surgery or curative radiation was evaluated in two open-label, multi-center, non-randomized, multicohort studies: Study 1423 (NCT02383212) and Study 1540 (NCT02760498). Both studies excluded patients with autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; prior treatment with anti–PD-1/PD-L1 blocking antibodies or other immune checkpoint inhibitor therapy; infection with HIV, hepatitis B or hepatitis C; or ECOG PS ≥ 2.

Patients received LIBTAYO 3 mg/kg intravenously every 2 weeks for up to 48 weeks in Study 1423 or up to 96 weeks in Study 1540. An additional cohort of patients in Study 1540 received 350 mg every 3 weeks for up to 54 weeks. Treatment continued until progression of disease, unacceptable toxicity, or completion of planned treatment. Tumor response assessments were performed every 8 or 9 weeks. The major efficacy outcome measures were confirmed objective response rate (ORR), defined as complete response (CR) plus partial response (PR) as assessed by independent central review (ICR), and ICR-assessed duration of response (DOR). For patients with mCSCC without externally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). For patients with externally visible target lesions (laCSCC and mCSCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria).

14.2 Basal Cell Carcinoma (BCC)

The efficacy of LIBTAYO in 112 patients with advanced basal cell carcinoma (BCC) [unresectable locally advanced (laBCC) or metastatic (nodal or distant) (mBCC)] who had progressed on hedgehog pathway inhibitor (HHI) therapy, had not had an objective response after 9 months on HHI therapy, or were intolerant of prior HHI therapy was evaluated in Study 1620 (NCT03132636), an open-label, multi-center, non-randomized study. The study excluded patients with autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; prior treatment with anti–PD-1/PD-L1 therapy or other immune checkpoint inhibitor therapy; infection with HIV, hepatitis B or hepatitis C; or ECOG performance score (PS) ≥ 2.

Patients received LIBTAYO 350 mg every 3 weeks for up to 93 weeks until disease progression, unacceptable toxicity, or completion of planned treatment. Tumor assessments were performed every 9 weeks for the first 45 weeks of treatment and every 12 weeks thereafter. The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) as assessed by independent central review (ICR). For patients with mBCC without externally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). For patients with externally visible target lesions (laBCC and mBCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria).

A total of 112 patients with advanced BCC were included in the efficacy analysis of Study 1620. Of these, 25% had mBCC and 75% had laBCC. In patients with laBCC, the median age was 70 years (42 to 89 years); 67% were male; 68% were White; 61% had ECOG PS 0 and 39% had ECOG PS 1; 83% had received at least 1 prior cancer-related surgery; and 50% had received prior radiotherapy. In patients with mBCC, the median age was 65.5 years (38 to 90 years); 82% were male; 79% were White; 57% had ECOG PS 0 and 43% had ECOG PS 1; 82% had received at least 1 prior cancer-related surgery; and 61% had received prior radiotherapy. Among patients with mBCC, 32% had distant metastases only, 14% had nodal disease only, and 54% had both distant and nodal disease.

Efficacy results are presented in Table 9. For the responding patients, the median time to response was 3.2 months (range 2.1 to 10.5 months) for the mBCC group and 4.2 months (range 2.1 to 13.4 months) for the laBCC group.

14.3 Non-Small Cell Lung Cancer (NSCLC)

The efficacy of LIBTAYO was evaluated in Study 1624 (NCT03088540), a randomized, multi-center, open-label, active-controlled trial in 710 patients with locally advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation, or with metastatic NSCLC.

Only patients whose tumors had high PD-L1 expression [Tumor Proportion Score (TPS) ≥ 50%] as determined by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible.

Patients with EGFR, ALK or ROS1 genomic tumor aberrations; a medical condition that required systemic immunosuppression; autoimmune disease that required systemic therapy within 2 years of treatment; or who had never smoked were ineligible. Patients with a history of brain metastases were eligible if they had been adequately treated and had neurologically returned to baseline for at least 2 weeks prior to randomization.

Randomization was stratified by histology (non-squamous vs squamous) and geographic region (Europe vs Asia vs Rest of world). Patients were randomized (1:1) to receive LIBTAYO 350 mg intravenously (IV) every 3 weeks for up to 108 weeks or a platinum-doublet chemotherapy regimen for 4 to 6 cycles followed by optional pemetrexed maintenance for patients with non-squamous histology who received a pemetrexed containing regimen.

Treatment with LIBTAYO continued until RECIST 1.1-defined progressive disease, unacceptable toxicity, or up to 108 weeks. Patients who experienced IRC-assessed RECIST 1.1-defined progressive disease on LIBTAYO therapy were permitted to continue treatment with LIBTAYO (up to an additional 108 weeks) with the addition of 4 cycles of histology-specific chemotherapy until further progression was observed. Of the 203 patients randomized to receive chemotherapy who had IRC-assessed RECIST 1.1- defined disease progression, 150 (74%) patients crossed over to treatment with LIBTAYO. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS). An additional efficacy outcome measure was overall response rate (ORR).

The study population characteristics were: median age of 63 years (range: 31 to 84 years), 45% age 65 or older; 85% male; 86% White, 11% Asian; and 0.6% Black. Nine percent were Hispanic or Latino. Twenty-seven percent had ECOG PS 0 and 73% had ECOG PS 1; 84% had metastatic disease and 16% had stage IIIB or IIIC disease and were not candidates for surgical resection or definitive chemoradiation per investigator assessment; 56% had non-squamous and 44% had squamous histology; and 12% had history of treated brain metastases at baseline.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to LIBTAYO as compared with chemotherapy.

Efficacy results are presented in Table 10 and Figure 1.

Figure 1: Kaplan-Meier Curve for OS from Study 1624

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Protect from light. Do not freeze or shake.

Immune-Mediated Adverse Reactions

Advise patients that LIBTAYO can cause immune-mediated adverse reactions including the following [see Warnings and Precautions (5.1)]:

• Pneumonitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsening symptoms of cough, chest pain, or shortness of breath.
• Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of colitis, including diarrhea, blood or mucus in stools, or severe abdominal pain.
• Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.
• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, or type 1 diabetes mellitus.
• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
• Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new rash.

Infusion-Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].

Complications of Allogeneic HSCT or Solid Organ Transplant Rejection

Advise patients to contact their healthcare provider immediately if they develop signs or symptoms of post-allogeneic HSCT complications or of solid organ transplant rejection [see Warnings and Precautions (5.1, 5.3)].

Embryo-Fetal Toxicity

Advise females of reproductive potential that LIBTAYO can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose of LIBTAYO [see Use in Specific Populations (8.3)].

Lactation

Advise female patients not to breastfeed while taking LIBTAYO and for at least 4 months after the last dose [see Use in Specific Populations (8.2)].